African Americans and Africans experience a disproportionate burden of aggressive breast cancer in comparison to all other racial/ethnic groups for reasons that remain unknown and understudied. The paucity of data on the genetic epidemiology of breast cancer for women of African ancestry hinders the development of innovative prevention to reduce health disparities. Because common genetic variants with potential large population attributable risk may play a role in breast cancer development and progression for women of African ancestry in a way different from women of European ancestry, we propose to replicate 5 novel breast cancer susceptibility loci (involving 11 genes) previously identified in genome-wide association studies in a well-characterized cohort of about 2200 breast cancer cases and 2300 controls, all of African ancestry. DNA samples and epidemiologic data for this large study have been collected through Nigerian Breast Cancer Study (Africans), Barbados National Cancer Study (African Barbadians), and the Chicago Breast SPORE and the Breast Cancer Family Registry (African Americans). We will employ the replication plus fine-mapping strategy to genotype exactly same SNPs identified in original studies and a panel of tagSNPs and putative functional variants in these 5 genomic regions. For African Americans, ancestry informative markers will also be genotyped to control for population stratification. Multiple imputation procedure will be used to impute variants that are not genotyped. Logistic regressions will be used to test the associations and calculate odd ratios. Furthermore, we will examine gene-environment interaction as there are sharp contrasts in epidemiologic risk factors among the three populations of African ancestry. This study will advance understanding the genetic risk factors for breast cancer in women of African descent and will be invaluable in developing novel prevention strategies in the future.